RT Journal Article
SR Electronic
T1 A Novel Vitamin D Derivative Activates Bone Morphogenetic Protein Signaling in MCF10 Breast Epithelial Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1840
OP 1848
DO 10.1124/mol.105.022079
VO 69
IS 6
A1 Hong Jin Lee
A1 Andrew Wislocki
A1 Catherine Goodman
A1 Yan Ji
A1 Rongrong Ge
A1 Hubert Maehr
A1 Milan Uskokovic
A1 Michael Reiss
A1 Nanjoo Suh
YR 2006
UL http://molpharm.aspetjournals.org/content/69/6/1840.abstract
AB We investigated the action of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], a novel Gemini vitamin D3 analog Ro-438-3582 [1α,25-dihydroxy-20S-21(3-hydroxy-3-methyl-butyl)-23-yne-26,27-hexafluorocholecalciferol (Ro3582)], and a classic vitamin D3 analog Ro-26-2198 [1α,25-dihydroxy-16,23(Z)-diene-26,27-hexafluoro-19-nor-cholecalciferol (Ro2198)] in modulating the transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) system in MCF10 immortalized breast epithelial cells. We found that 1α,25(OH)2D3, Ro3582, and Ro2198 all enhanced BMP/Smad signaling by increasing the phosphorylation of receptor-regulated Smads. Ro3582 was more active than Ro2198, but both were considerably more active than 1α,25(OH)2D3. Ro3582 enhanced BMP/Smad signaling by 1) inducing the phosphorylation of receptor-regulated Smads (Smad1/5), 2) increasing the accumulation of phosphorylated Smad1/5 in the nucleus, and 3) activating BMP-mediated transcription in MCF10 breast epithelial cells. Furthermore, Ro3582 induced the synthesis of BMP-2 and BMP-6 mRNA and protein, and the expression of Smad6 mRNA in MCF10 breast epithelial cells was inhibited by Ro3582. The induction of phospho-Smad1/5 by Ro3582 was inhibited by treatment with the BMP antagonist Noggin, whereas neutralizing antibody to TGF-β did not block the induction of phospho-Smad1/5 by Ro3582. Treatment with Noggin also blocked the effect of Ro3582 on nuclear accumulation of phospho-Smad1/5 and the induction of BMP-2 and BMP-6 mRNA synthesis. These results indicate that the activation of BMP/Smad signaling by the Gemini vitamin D3 analog Ro3582 may be through the production of BMP ligands, including BMP-2 and BMP-6, and/or down-regulation of the inhibitory Smad6. This is the first report to show that 1α,25(OH)2D3 and its derivatives activate BMP/Smad-specific signaling in human breast epithelial cells.